Personalised Medicine Policy Forum –

26th October

The 100,000 Genomes Project

Dr Tom Fowler, Director of Public Health

The 100,000 Genomes Project

29 October 2015 2

Background

Announced by the Prime Minister in

December 2012

An Olympic Legacy

Genomics England announced by Secretary of State for

Health in speech during NHS 65th Anniversary

Celebrations, July 2013

The first human genome

sequence

29 October 2015 3

100,000 Genomes at Millennium Prices - Cost $320 trillion

26th June 2000 - Cost $3.2 billion

Cost per Million bases of sequencing

29 October 2015 4

Four main aims

29 October 2015 5

1. To bring benefit to NHS

patients

2. To create an ethical and transparent

programme based on consent

3. To enable new scientific

discovery and medical insights

4. To kickstart the development of a

UK genomics industry

Rare disease

29 October 2015 7

The case for deep phenotypic data in rare

disease

Subphenotypes

Po

wer

1 2 5 10

010

20

30

40

50

60

70

80

90

100

Quality of subphenotyping:100% (Perfect)80%50%10% (Random)

Luke Jostins and Gil McVean

29 October 2015 8

Phenotyping in Rare Disease

• Working on 110 phenotypes

• Detailed and genomically primed clinical phenotyping

• Diagnostic tests- genomic, imaging, pathology

• Human Phenotype Ontology

• Disease progression

• Additional phenotypes guided by clinicians

• Building a National Rare Disease Registry

• Linked to Primary Care, Hospital Episodes and Outcomes

29 October 2015 9

First families diagnosed from the

Newcastle BioResource pilot

1. Leslie Hedley, 57

WGS revealed Mr Hedley’s kidney failure was caused by a particular genetic variant (INF2 mutation).

His family is also being tested and their blood pressure can now be effectively controlled by drugs

available on the NHS.

2. William and Allan Carpenter aged 79 and 69

Suffered from muscle loss and weakness. They have now been diagnosed with inherited nerve

damage, known as peripheral neuropathy.

The brothers may be joining a treatment trial which, if successful, could prevent family members

developing the same condition.

29 October 2015 10

Father and daughter: inherited kidney

disease

29 October 2015 11

Diagnostic Odyssey

Distal sensory-motor neuropathy

Additional

investigations

Nerve conduction

studies (x 4) - £1600

Total cost: £2905 (excluding routine biochemical investigations)

29 October 2015 12

Cancer

Cancer

• Disease of disordered genomes – over 200 drivers known

• Drugs target mutations. Tumour heterogeneity/ evolution of cancer/ Stratified medicine

• Lung, breast, colon, prostate, ovary and, Leukaemia and

• Rare and Childhood Cancers, unknown primary

• Diagnosis and therapy is evolving

• International Cancer Genomes Consortium- the Cancer Genome Atlas

• Cancer Research UK Stratified Medicine Programme

• UK Leukaemia consortia

• NIHR Biomedical Research Centres

Lung cancer before and after Gefitinib

Phenotyping in Cancer

• Phenotype models - commonality ICGC

• Diagnostics and Imaging

• Molecular Pathology & genomic tests

• Linked to NHS disease specific cancer registries

• MDT Information- Chemo & Radiotherapy

• Outcomes

Pathology Processing: Tissue

Pathogens

Infections

Pathogens

• Stratifying response, minimising adverse events and tracking outbreaks

• M. Tuberculosis resistance and epidemiology

• Hepatitis C genotype selects therapy

• HIV –Treatment for life and resistance testing is in the care pathway.

• Extreme human response to sepsis

• International linked datasets

NHSE

and GMCs

GeCIPs

Commercial

Partnerships

Genomics

EnglandIllumina

The Principal Partners

29 October 2015 22

Establishment Phase

• Illumina - NHS Genomic Medicine Sequencing Centre in Hinxton

• UK Data Infrastructure for Genomic Medicine (with MRC)

• NIHR National Biosample Centre - £24 million state-of-the-art facility to store the samples

• 11 NHS Genomic Medicine Centres in England to enrol, validate and feedback to patients

29 October 2015 23

Data CentreNHS Genomic Medicine Sequencing Centre NIHR Biosample centre

Genomics England specific Responsibilities

Sequencing

Centre

Biorepository

Consent

Clinical DataSamples

SamplesSamples

Clinician

Genomics England Informatics

Infrastructure

Scientific + Clinical

Users

Commercial

Users

Pipelines from sequence to patient

Sequence

DataData Validation

MD5

BAM and VCF

QC

Orchestration

Engine

Archiving on

tape

StateDB

Participant

data from

LabKey

Variant store

Genotypes and

Annotation

Variant

Annotation

Annotation store

CellBase

yes

Data Verification

Participant

Catalogue

Consistent?

No

Reconciliation

Checks:

Sex

Ethnicity

Tumour-

Normal pairing

Family

relationships

Contamination

(normal, non-

human, other

human)

LOH checks

Heterozygocity

estimation

Eye colour/hair

colour traits.

Export

Pass?Illumina redelivery No

Delivery APIClinical

Interpretation

Report Request

BAMs

gVCFs

Sex

Pedigree

Phenotypes

Annotation

Presumed

MOI/Family

history/

Pedigree?

Consent

status

Cancer type

Primary vs

met

Stage

Secondary Analysis

Alignment and

Variant calling

Variant score

calibration and

filtering

Report Generation

Ranked

Candidate

Variants

RARE

DISEASES

Karyotype

Ranked

Candidate

Variants on

drivers

Fusion genes

Plots

Other

relevant info

CANCER

Gene Lists

KP variants

BAM

statistics

Aggregate

statistics

Calculation

GEL sample tracking

Report

Report DB

Sequence

Data

Report Adjudication

and Interna Clinicall

Signoff

Report review

Report triaging

and

distribution

Variant

Justification

Variant Review

Tool, process or

service

External process

Subprocess

Database

Data record

(and

schema)

Report

distribution

Clinical Decision and

Reporting Support

Tool

Feedback to

participant

Variant

technical

validation and

positive

patient

identification

Clinical

Scientist

Signoff

Further

functional

validation,

cascade

testing,

transmission

testing

GMC

Validated

Report

Feedback

Feedback to

patient

Referral to GECIPGECIP

Multidisciplina

ry team

support

application

Further

functional

validation,

cascade

testing,

transmission

testing

Decision

capture tool

Decision

capture tool

GECIP-

enhanced

Report

Report DB

Annotation

storeCuration

Gene Lists

KP variants

Ranked

Candidate

Variants

ADDITIONAL

FINDINGS

Knowledge

Croudsourcing

Tool

Novel

validated

variants or

genes

Review of novel

variants

Gene discovery

Cohort analysis

tool

External

Knowledge

Bases

Clincial Reporting Pipeline

2015-03-12Confidential – Commercially Sensitive

Randomized file

paths?

Federation

BAM stats

Tiering

Participants Data

Sequence Data

Annotation

Knowledge Bases

Access to Enhanced

Catalogue

To Report DB

To Report DB

Allele frequencies

Black lists

Hardy weinberg

Other metrics

From

Annotation

store

29 October 2015 25

NHS Genomic Medicine Centres

• Eleven Genomic Medicine Centres (GMCs) established in December 2014 by NHS England. These centres will lead the way in delivering the 100,000 Genomes Project.

• Track-record of providing excellence in genomic services.

• Eligible patients will be referred to GMCs by their clinicians.

• First patients recruited by Manchester GMC in March.

29 October 2015 26

29 October 2015

What will we be telling

participants?

• Information about a patient’s main condition

• Information about ‘serious and actionable’ conditions (optional)

• Carrier status for non affected parents of children with rare disease (optional)

Image courtesy of Health Education England

Clinical Interpretation Partnerships• We ran a world-wide competition to test the state-of-the-art in

annotation and interpretation of genomic data

• It is clear that scientific and clinical understanding is far from mature

• So we have initiated the creation of a network to draw in the best clinical and scientific minds from the UK and around the world to access our data and interpret the results

Sample

collection

DNA

extraction

Biorepository

Sequencing

Variant

Calling

Interpretation

Feedback

to clinician

Validation

Treatment

Work of ~30

disease groups

involving upwards

of 2500 Clinicians

and Scientists

The Genomics England Clinical Interpretation Partnerships

are

• Defined by diseases or cross cutting themes. We expect

between 30-50 GeCIP Domains in all

• Each must have a clear and unique focus and be open to

all experts in that field. Many to number more than 100

members

• Once designated GeCIPs have free access to the data

infrastructure and the dataset

• All IP held by Genomics England but available for licence

GeCIP Domains

Cardiovascular

Endocrine and Metabolism

Gastroenterology and

Hepatology

Hearing and Sight

Immunology and Haematology

Inherited Cancer Predisposition

Musculoskeletal

Neurological

Paediatric Sepsis

Paediatrics

Renal

Respiratory

Skin

Breast

Colorectal

Lung

Ovarian

Prostate

Childhood Solid Cancers

Haematological Malignancy

Pan Cancer

Renal

Sarcoma

Electronic Records

Validation and Feedback

Ethics and Social Science

Functional Effects

Health Economics

Machine Learning, Quantitative

Methods and Functional

Genomics

Population Genomics

Translational Research

Functional Cross Cutting

Stratified healthcare

Rare Cancer Functional

Health Education England

• 9 University providers of MSc in Genomic Medicine – aimed at NHS healthcare professionals working in England

• HEE - Genomics Education Programme, online training courses and resources

• University of Birmingham

• Newcastle University

• University of Manchester

• University of Sheffield

• Imperial College London

• Queen Marys University of London

• St Georges, University of London

• University of Cambridge

• University of Southampton

29 October 2015 30

Upskilling the workforce

GENE Consortium

• Ten companies have come together to create the Genomics Expert Network for Enterprises (GENE) Consortium to oversee a year-long Industry Trial

• Aims to identify most effective and secure way of bringing industry expertise into the 100,000 Genomes Project in order to realise the potential benefits for patients.

• AbbVie, Alexion, AstraZeneca, Berg, Biogen, Dimension Therapeutics, GSK, Helomics, Roche, Takeda

29 October 2015 31

Working with industry

Progress so far

29 October 2015 32

• Over 5,000 participants have already agreed to take part as part of the pilots: 3,500 in rare diseases and almost 2,000 in cancer.

• We have already delivered 5,000 whole genome sequences, and we are starting to interpret these to help patients.

• These first 5,000 sequences are from the pilot phase and our GeCIPdomains and GENE Consortium partners will shortly begin working with this data

• http://www.genomicsengland.co.uk/100000-genomes-project-update/

PanelApp

• A publically-available resource that allows gene panels to be viewed, downloaded and evaluated by the Scientific Community.

• Initial gene panels have been established for all the approved rare diseases (Version 0), and graded using a traffic light system to indicate the number of sources.

• We are seeking expert review of these panels.

Aims:

• Source expert knowledge to establish a final diagnostic grade gene panel (or “green list”) for each disorder that will be used in the classification of genetic variants to aid clinical interpretation of rare disease genomes (Version 1).

• Engage the Scientific Community, encourage open debate, and begin to establish consensus on gene panels for rare diseases.

• A mechanism to allow access to the panels, standardisation of terms and collection of gene-disease related information, accumulation of reviews over time, and updated releases (Version 2…).

33

A crowdsourcing tool for gene panels

PanelApp

34

https://bioinfo.extge.co.uk/crowdsourcing/PanelApp/

Public access

• View and download

gene panels.

• View Reviewers’

comments.

Public access

• View and download

gene panels.

• View Reviewers’

comments.

Register to be a

reviewer

• View and download

gene panels.

• View Reviewers’

comments.

+ Evaluate genes and

make comments.

+ Add genes to a gene

panel.

Register to be a

reviewer

• View and download

gene panels.

• View Reviewers’

comments.

+ Evaluate genes and

make comments.

+ Add genes to a gene

panel.

PanelApp information

35

https://bioinfo.extge.co.uk/crowdsourcing/PanelApp/

PanelApp Gene Panel View

36

Example: Familial Diabetes panel

In 10 years - Genomics England

• 100,000 WGS on NHS patients and pathogens

• WGS deployed routinely- also in other diseases

• Harnessing electronic health records

• Patient reported outcomes and more remote monitoring

• New diagnostics and therapies and opportunities for patients

• By end of 2017

29 October 2015 37

Stay in touch

www.genomicsengland.co.uk

info@Genomicsengland.co.uk

@genomicsengland

#genomes100k

Follow ‘Genomics England’